Heating of cancer tissue has been found to be beneficial in several ways. First, the heat may directly kill tumor cells, especially hypoxic cells in the center of the tumor. Secondly, the heated cells will liberate tumor antigens and thus sensitize the immune system to specific cancer tumor antigens, which helps to control the growth of cancer tissue. Thirdly, heat destroys the fragile neovasculature which develops in the tumor. These listed benefits are not the only beneficial effects of heat in cancer therapy since heat intensifies the killing effect of ionizing radiation or chemotherapy or both. As an example, the killing effect of chemotherapeutic agents is often enhanced in excess of more than two orders of magnitude. For these reasons, heat must be included in the therapeutic considerations for the treatment of all human cancers along with radiation and chemotherapy.
This invention relates to the treatment of tumors in animal hosts, such as human beings, and in particular provides a technique for destroying the tumor without injury to adjacent normal tissue. The tumors can be benign or malignant and include carcinomas, sarcomas, and avascular lesions.
It is an important aspect of this invention to provide an apparatus applicable to the treatment of tumors under a wide variety of conditions which can be utilized with a minimum, and preferably an absence, of surgery.
It has been noted that tumors can be affected by hyperthermia (Brit. of Cancer 25:771, 1971; Cancer Research 32:1916, 1972) and this observation was coupled with the notation that the tumors were heat sensitive. Experiments with external surface heating do not produce deep heating and in some cases, using hyperthermia, the whole animal was heated as much as the tumor. Others have felt that a slight raise in temperature produced by metabolic changes interfered with cell growth (Europe. J. Cancer 9:103, 1973). Still others have heated tumors a few degrees by diathermy and observed that the effect on the tumor was inhibitory but not destructive (Zeit. fur Naturforschung 8, 6:359, 1971). There is still some disagreement in the role heat may play in the treatment of cancer (The Lancet, May 3, 1975;1027).
Anatomical studies suggest the blood flow through carcinomas and other neoplasms is sluggish (Acta Pathalogica Microbiological Scand., 22:625, 1945; Advances in Biology of the Skin, 21:123, 1961). Furthermore, tumors possess an angio-genetic factor which initiates the formation of new blood vessels. The blood vessels which are stimulated to grow are capillaries, which because of their small diameter offer great resistance to blood flow. These tumor initiated capillaries make connections with the normal capillaries on the periphery of the tumor and form tortuous haphazard pathways before emptying into some small veins at the periphery of the tumor. Frequently, there is marked venous obstruction within the tumor caused by compression of the peripheral veins due to enlargement of the tumor and growth of tumor cells into the blood vessels obstructing them.
Anatomical studies also demonstrate the presence of arterio-venous fistulae at the periphery of tumors which can cause the tumors to appear vascular and on angiography cause the rapid appearance of contrast media. However, these fistulac at the periphery of the tumor tend to create a low resistance pathway at the surface of the tumor which lowers the arterial pressure and diverts blood from entering the tumor.
Although anatomical studies suggest that tumor blood flow is diminished and slow, angiographic studies have functionally confirmed that blood flow through a tumor is actually sluggish. Residual contrast medium remains in the tumor after it has been swept out of the adjacent normal tissue by normal blood flow. This remaining residual contrast medium has been called a "Tumor Stain". The tumors which have been most studied radiographically have been brain tumors and kidney tumors.
A sluggish flow has been confirmed by the indicator dilution technique which measures the actual flow of blood through normal tissue and through tumors. The indicator dilution technique is more reliable than the visual method as seen on angiography. Such studies were done in vivo using x-ray contrast medium dilution and in vivo on excised specimens. In the excised specimens, blood flow was measured by an indicator dilution technique before using radio-iodinated serum albumin. The albumin molecule was tagged with I.sub.131 and the isotope dilution was measured in the tumor and in normal tissue by a collimated scintillation counter. These studies indicated that the magnitude of flow through the adjacent normal tissue is such that the tumor tissue is differentially heated when the area of body containing the tumor is treated by diathermy.
It is known that tumors are usually destroyed by a quantum of heat which would be delivered by a temperature of 45.degree. C. over a period of three hours. Exposure at higher temperature requires less time. At 50.degree. C., the time is reduced to a mere ten minutes. Such temperatures, of course, also destroy or severely damage normal tissue and the present invention utilizes one of the Applicant's prior discoveries. When a portion of the body is heated, for example, by applied radio frequency electromagnetic radiation, the tumor is heated differentially to a greater extent, such that the temperature of the normal tissue adjacent the tumor can be kept below 40.degree. C.
This effect is caused primarily by the normal blood flow in the adjacent normal, non-cancerous tissue, because the temperature at which tissue is heated is a function of the blood supply to the tissue. Although the blood itself is heated, it serves as a heat exchanger to carry heat away from the tissue being heated. Tissues which are poorly perfused with blood such as cancerous tissue become heated more rapidly and to a higher temperature than tissues which have a normal rate of blood flow. As pointed out above, cancerous and other malignant and benign growths develop outside a preformed blood distribution network and derive their blood supply from the periphery of the tumor where it meets the adjacent normal blood supply. As a consequence, the slow rate of volume and blood flow through the tumor provides a lesser cooling rate in the tumor than the flow of blood through the normal tissues adjacent to the tumor.
Such treatment of cancer has finally been disclosed in U.S. Pat. No. Re 32,066 dated Jan. 21, 1986 and, the references cited therein.
The apparatus for heating tumors in the '066 patent employed an amplifier which amplified the output of a crystal oscillating at 13.56 or 27.12 megaHertz. Crystal oscillators were used to insure that the generated frequencies were within the band allocated to medical use, otherwise it would be necessary to place the patient together with the R. F. generator into a Faraday cage to shield against leakage into the environment. However, studies on patients during RF treatment disclosed that the amount of RF in the immediate environment was usually greater than permitted by OSHA standards.
U.S. Pat. No. 4,285,346 describes an impedance matching unit which may be used between a radio frequency generator or source and a pair of electrodes placed adjacent a body. This reference also describes arrangements using a plurality of pairs of electrodes, pairs of which may be rendered separately inoperative by grounding of the transmission cable extending from the matching unit to a pair of electrodes.
U.S. Pat. No. 4,356,458 describes an apparatus for automatically adjusting the impedance of an electrical circuit connected to a radio frequency source so as to maintain the impedance of the circuit at a substantially constant value to permit the maximum transfer of energy to the load forming part of the circuit, and relates particularly to apparatus for use with, the short wave diathermy apparatus described in the above mentioned '346 patent.
U.S. Pat. No. 4,230,129 relates to a "C" shaped apparatus with electromagnetic energy applicator plates. The exact position and configuration of the tumor is plotted in terms of rectangular coordinates and the radio frequency equipment can then be directed or focused on the tumor location in order to avoid excessive heating or thermal damage to the surrounding tissue. The applicator plates or discs are moved in an orbital manner such that the tumor always lies on the axis between the applicator plates and the radio frequency energy is concentrated therein. Because of the orbital movement of the apparatus, the energy is not continuously being applied to a confined area, i.e., to immediately surrounding tissue, but rather is applied over a comparatively large surface area so as not to affect the surrounding tissue adversely.
Yet, as beneficial as heat has proven to be, it is often difficult or impossible to raise the tumor temperature sufficiently to produce the maximum tumor benefit without burning the skin or injuring adjacent organs and causing serious discomfort to the patient. In addition to these serious disadvantages to RF heating, the apparatus is expensive and remains ineffective for heating tumors deep in the body. For these reasons, an inexpensive method to introduce heat and localize it to a specific volume has presented a heretofore insoluble problem. If the heating is done by extremely short wavelengths, such as those in the microwave range (waves with a frequency in the region of 1,000 megaHertz) the absorption of energy in the superficial tissue is so great that the amount of energy reaching a deep-seated tumor will be insufficiently low. However, microwaves can be easily focused to direct them to the site of the tumor, while longer wavelengths, such as those in the range of 13.36 or 27.12 megaHertz, are of such length that they cannot easily be focused on target volumes as small as solid tumors. Yet, the absorption of these waves is far less and would be more useful if a method could be found to contain and direct their energy to a specific target.
Moreover, the lower the RF frequency, the larger the contribution of the quasi-static current term with respect to the radiation term in the deposited energy in lost tissue. Low frequency RF currents do not present any problem of penetration, therefore, it would be useful if a method was devised to direct and confine low frequency energy in such a way that a flux tube of high density energy could be confined to a circumscribed volume of tissue.
The specific absorption rate (SAR) of electromagnetic energy in a conductive tissue is proportional to .sigma.E.sup.2 where .sigma. is the local conductivity and E is the intensity of the local electric field in the tissue. If we limit our considerations to EM fields and associated currents in the RF range, the local E field (electric) may be made flowing into the body from para-corporal electrodes sometimes called the capacitive or dielectric heating method since the body can be considered a lossy dielectric between two capacitors). However, the E field may be indirectly created in the tissues by a magnetic coupling of the applicator to tissue through the H field (magnetic) generated by an inductive applicator sometimes called inductive heating because an electric field is induced in conductive tissue). In the capacitive method, the E fields from the electrodes present a forceful component perpendicular to the fatty subcutaneous tissue, thus heating the highly resistive fat with respect to the deeper (muscle) layer beneath the fat. If the inductive method is used instead of the capacitive method, the induced E fields and associated eddy currents are flowing parallel to the fat-muscle interface which minimizes heating of the non-conductive fat layer and allows for passage of considerably more energy to the deeper muscle or tumor tissue. The inductive method makes it possible to treat obese patients who cannot be treated by the capacitive method. The inductive heat method also allows for greater heat to be developed in tumors which are surrounded by tissue of high impedance. For example, cancers of the lung have a much lower impedance than the surrounding air containing lung which, because of its air content, presents a high impedance. Inductive heating will heat the high impedance lung tissue less and the conductive cancer tissue will receive more heat. A similar situation is encountered in abdominal cancers where the cancer, having a relatively low impedance, is surrounded by loops of gas filled bowel whose impedance is high due to their gas content. Thus, inductive heating allows the energy to be deposited in the more conductive cancerous tissue.
Inductive RF heating devices have taken the shape of coils with the coil design derived mainly from inductive diathermy practice. (See Lehman, J. F."Therapeutic Heat and Cold", Williams & Wilkins, Baltimore, 1982; Oleson, J., IEEE Trans. Biomed Eng. Vol. BME-31, pp, 91-97; 1984). The described practice for external coil applicators is with the coil plane parallel or perpendicular to the body surface which changes the direction of the H field with respect to the body surface. EM theory teaches us that an H field always induces an E field and associated RF current loops always lie in planes perpendicular to the H field lines of force, and therefore parallel to the RF currents flowing in the metal coil. The heat deposition with these current carrying coils results in an intense gradient towards the loop center where no heat is deposited. A typical coil H field distribution in a cross section of a coil much larger than the tumor mass would produce little RF power deposition in the tumor and the heating would be maximum only near the inner coil surface and the induced E field would rapidly decrease to zero at the coil center. Improved results are expected by the use of low inductance cylindrical RF coils which generate a more uniform cross sectional field distribution than single turn coils. Nonetheless, the results obtained with both the cylindrical RF single turn coils lying parallel to the body surface load (Kato,H. J.Med.Sci. 7:35-46; 1983) and with the cylindrical coil RF single turn coil, coaxially loaded (Elliot,RS et al IEEE Trans.Biomed.Eng.BME-29:61-64, 1982) displays a high degree of non-uniformity in the distribution of the H field on cross section. A further disadvantage of the coil design is that the magnetic dipole flux lines are not contained but are rather spread all around the open space which results in a dramatic decrease of RF energy density immediately outside the coil's cylindrical body. This puts a great deal of RF energy into the ambient environment and would expose the operators of the equipment to a dose of radio frequency beyond that allowed by OSHA standards and the standards of other countries. Therefore, the patient must be put in a Faraday cage to safeguard the operator. We have verified in the laboratory the low RF energy effectiveness of coil applicators when coupled in a perpendicular coil to body configuration. (IEEE Trans.Micr.Theory and Tech.MTT-34:612-619; 1986). In addition, the patients are also exposed to unnecessarily high stray H fields which were not heating the tumor.
It may be concluded that previous coil design applicators are unsuitable for generating high density uniform magnetic fields in a circumscribed cross section which could be usefully directed and localized to a malignant tumor mass since the heating pattern cannot be controlled for safe and effective cancer therapy.